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Deriving 'Controversy-Free' ES Cells Is Controversial

Gretchen Vogel

Two methods that create embryonic stem (ES) cells without destroying viable embryos can work—at least in mice. But although some scientists and ethicists herald the research as a step toward finding an uncontroversial way to produce ES cells, it seems clear that neither method completely resolves the ethical debate.

One method, called altered nuclear transfer (ANT), uses nuclear transfer to create cells that are incapable of forming a normal embryo but can give rise to ES cells. In the second, researchers derive an ES cell line from a single cell taken from an early embryo—while allowing the remaining cells to develop into a live-born mouse. Ethicists and researchers have proffered both ideas in the past as alternative ways to create ES cells, which can become any kind of cell in the body, without destroying an embryo (Science, 24 December 2004, p. 2174). Until now, however, the discussions have been largely theoretical.

Developmental biologists Rudolf Jaenisch and Alexander Meissner of the Whitehead Institute at the Massachusetts Institute of Technology wanted to see if they could move ANT theory into practice. As they describe in a paper published online 16 October in Nature, they did so by interrupting the function of a gene called Cdx2 in a donor skin cell and fusing that cell with an oocyte. This created cells that could form a type of early-stage embryo called a blastocyst and give rise to ES cells—but could not implant in a uterus and therefore had no chance of developing into a full organism.

William Hurlbut, a physician and ethicist at Stanford University and a strong proponent of the ANT idea on the President's Council on Bioethics, says that without Cdx2, the cell clusters lack the basic organizational capability that would merit the term “living organism.” The lack of Cdx2, he explains, “is not a deficiency but an insufficiency. I think it's pretty reasonable to say [the resulting cells] are not a human.”

Jaenisch says that although he and Meissner have no moral objections to research that uses human embryos, they pursued the ANT project to see if there might be a simple way to break the political and ethical impasse. In the United States, federal law prohibits funding for research that harms or destroys human embryos—including human nuclear transfer experiments. “Nuclear transfer is such an important technology, and if we want to do it in the States, we need federal funding. If this serves as a compromise, the modifications are so simple that one could accept them,” Jaenisch says.

To others, however, the technique raises more questions than it answers, both ethical and scientific. Turning off Cdx2 creates a severely disabled embryo but an embryo nonetheless, says Tadeusz Pacholczyk of the National Catholic Bioethics Center in Philadelphia. Stem cell researcher George Daley of Children's Hospital in Boston says the data Jaenisch and Meissner show suggest Pacholczyk has a point. “The embryo that is established in the first few days is substantially normal,” he says.

Ethical end run?

Altered nuclear transfer produces blastocysts that lack a gene required for early development. The abnormal blastocysts can give rise to ES cells but cannot implant in a uterus.

CREDIT: ILLUSTRATION: CHRIS BICKEL/SCIENCE

Even so, Pacholczyk is encouraged by the work. “This study doesn't get around the ethical impasse yet. But … it does remind us how the power of science can be used to resolve some very grave moral concerns.”

Although Jaenisch says their ANT method is not difficult to perform, it does introduce an additional complication. The technique involves inserting extra DNA into the donor cell genome, which can sometimes interrupt other genes and leave the cell's progeny prone to forming cancerous tumors. Jaenisch says that risk is small and preventable: Researchers can check their donor cells before nuclear transfer to see where the added DNA has integrated. The pair also demonstrated that the DNA that interferes with Cdx2 production can be removed from the resulting stem cells so that any later use of the cell line would not be affected by the blocked gene.

In a second paper also published in Nature, Robert Lanza and his colleagues at Advanced Cell Technology (ACT), a biotech company in Worcester, Massachusetts, showed that they can remove a single cell from a very early mouse embryo and grow it into a stem cell line. The technique the scientists used is similar to that used in preimplantation genetic diagnostics, performed at fertility clinics around the world. Scientists remove one or two cells from early embryos to test them for the presence of certain genes, so that an embryo is implanted only if it doesn't carry a genetic disease.

The ACT team showed that for mouse embryos at least, a single cell taken from an eight-cell embryo can grow into ES cell lines when it is cultured with other ES cells. The technique isn't as efficient as obtaining ES cells from later-stage embryos, although Lanza says his team is working on it: The team produced just five ES cell lines from 125 tries, while the usual success rate is about 30%.

Lanza and his colleagues showed that the seven-cell embryos had the same chance of survival after implantation into a surrogate mother as undisturbed control embryos had. He believes that fertility clinics could use similar techniques to derive new human ES cell lines under existing regulations and safety guidelines—and might even be eligible for federal funding.

But the ACT method raises issues of its own, says fertility and stem cell research expert John Gearhart of Johns Hopkins University in Baltimore, Maryland, among others. It is not clear whether in mice or in humans the cell taken from the early embryo might itself be able to form a complete organism—a genetic twin of the original embryo—in which case, some argue, the technique would still destroy a potential life. In addition, the biopsy procedure carries “a small but known risk,” Gearhart says, not only to the embryo but also to the potential mother, because she might have to go through additional in vitro fertilization cycles if the embryo fails to develop.

Both proponents and critics agree that the ideal solution would be a way to reprogram a skin cell directly to an ES-like cell—without involving any embryolike entities. “That's the Holy Grail,” says Lanza. Daley predicts that with increased understanding of the genes that control ES cells, such a method will eventually be possible. “Then you'd have a reasonable technical fix,” he says—one that everyone could agree on.

STEM CELLS

U.S. Public Supports Stem Cell Research

Constance Holden

CREDIT: C. HOLDEN FROM GENETICS AND PUBLIC POLICY DATA

Although Senate leaders say their vote on proposals to loosen restrictions on federal stem cell policy may have to wait until next year, it looks as though Americans want change. Two-thirds of Americans approve of expanding use of human embryonic stem (hES) cells in research, saying they either support proposed legislative changes or favor more aggressively promoting this research. Johns Hopkins University's Genetics and Public Policy Center in Baltimore, Maryland, released the poll of 2212 people last week.

AVIAN INFLUENZA

Europe Scrambles to Control Deadly H5N1 Strain

Dennis Normile

After confirming last week that the deadly H5N1 avian influenza virus circulating in Asia has now killed 1800 turkeys at a farm in Turkey and several ducks in Romania, European officials are bracing for further outbreaks among poultry. “It's a worrying development,” says Michael Ryan, director of the Department of Epidemic and Pandemic Alert and Response for the World Health Organization (WHO) in Geneva, Switzerland. With migratory birds suspected of carrying the virus, “we may see further introductions [in other countries] in the coming weeks,” he adds. As Science went to press, there were reports that an H5 bird flu strain had surfaced in Greece.

Alex Thiermann, a veterinarian at the World Organisation for Animal Health (OIE) in Paris, praises Turkey and Romania for their “early detection, rapid response, transparency, and cooperation with international agencies.” Culling flocks quickly in an affected area, which the two countries are doing, is the best way to control local spread of the disease, he says. In Southeast Asia, the disease wasn't recognized until it had already spread widely among poultry.

Quick action.

Turkey's rapid response in collecting poultry for culling could minimize the inroads of H5N1 in the country.

CREDIT: ANATOLIAN/REUTERS

H5N1, previously concentrated along Asia's Pacific coast, started moving across the continent toward Europe in July. Although the role of wild birds in this spread is still debated (see p. 426), the European Commission is urging farmers near wetlands to minimize the chance of contact between poultry and migratory birds.

So far, the virus has infected 117 people in Asia, mostly from direct contact with infected birds, and has killed 60 of them. H5N1 “is an avian virus and not a pandemic virus,” emphasizes Ryan, who adds that its spread to Europe only slightly increases the chance that H5N1 will acquire the ability to pass easily among humans.

To prepare for a possible pandemic, many nations are stockpiling the antiflu drug oseltamivir (Tamiflu), considered the most effective antiviral available. But in the 20 October issue of Nature, a team led by Yoshihiro Kawaoka of the University of Tokyo, Japan, and the University of Wisconsin, Madison, reported that an H5N1 strain that infected a Vietnamese girl in February was resistant to oseltamivir. Kawaoka emphasizes that the vast majority of H5N1 strains in circulation are still sensitive to the drug, and “there is no point in changing the strategy for an outbreak” among humans. His team does suggest that as a backup, authorities consider stockpiling zanamivir, an antiviral that appears to maintain its effectiveness even against oseltamivir-resistant strains.

EVOLUTION

New Migration Route Could Lead to New Species of Bird

Elizabeth Pennisi

The cliché “birds of a feather flock together” doesn't hold for European blackcaps that breed in southern Germany and Austria. At one time, these birds migrated back and forth together, spending summers in northern Europe and winters in Portugal, Spain, and North Africa. But in the past 50 years, there's been a split in the avian ranks, with more and more heading northwest for the winter, not south.

Gone astray.

European blackcaps that moved to new wintering grounds outdo blackcaps taking the traditional route.

CREDIT: TIM LOSEB

On page 502, Stuart Bearhop, an animal ecologist at Queen's University Belfast, U.K., and his colleagues report that even though all the blackcaps gather each year at the same mating sites, they tend to reproduce with those from their particular wintering ground—a phenomenon called assortative mating. Moreover, the birds that stay north are reproducing more than those taking the southern route, which may improve the chances of the birds forming two species.

Researchers considering how new species develop have speculated that differences in migration patterns could produce assortative mating, but “this is the first empirical demonstration that it actually occurs,” says Michael Webster, a behavioral ecologist at Washington State University in Pullman. Moreover, he adds, the blackcap research helps explain how alternative migration patterns can evolve quickly.

Blackcaps were once typically seen in the United Kingdom only during the summer, but over the past 40 years, the number of them wintering in the U.K. has soared, prompting researchers to wonder how the birds' migration patterns were changing. Tracking migratory birds has posed quite a challenge. In 1997, however, researchers began using the ratio of hydrogen isotopes in bird tissue as a tool. Distinctive isotope patterns in rainfall, taken up by migrating birds, provide a signature to reveal where they have traveled.

In 2002 and 2003, Bearhop and Wolfgang Fiedler, an ornithologist at the Max Planck Institute for Ornithology in Radolfzell, Germany, used this technique to determine the winter origins of blackcaps landing in eight mating places in southern Germany and Austria. With these data, Bearhop, Fiedler, and Jason Newton of the Scottish Universities Environmental Research Centre in Glasgow found that blackcaps from the same winter home were 2.5 times more likely to mate with each other than with blackcaps from elsewhere. The findings “strongly indicate that this is assortative mating due to the different wintering areas,” notes Darren Irwin, an evolutionary biologist at the University of British Columbia in Vancouver, Canada.

Assortative mating is a matter of timing, Bearhop says. The birds from Britain and Ireland have shorter migrations to their summer mating grounds in Germany and Austria and, prompted by the more dramatic changes in day length at their home locations as winter becomes spring, those more northern migrants leave about 2 weeks earlier than those wintering in Iberia. “Because [these birds] mate with whoever arrives first, they have tended to remain isolated from the later-arriving historical population,” say Keith Hobson, an ecologist with the Canadian Wildlife Service in Saskatoon, Canada.

The recent shift in migratory pattern is a boon to the northern blackcaps. These frontrunners grab the prime real estate and seduce early-arriving females. They tend to lay about one more egg per season than the late arrivals from the south, says Bearhop. “[These data] may help explain why there has been such an increase in blackcaps wintering in Britain,” Irwin notes.

Still, Hobson and others question whether the north-based birds are becoming a new species. They argue, for example, that there is not yet enough information about the fate of hybrids between the two bird populations. Nonetheless, says Peter Marra of the National Zoological Park in Washington, D.C., “this study provides us with a scenario of how [separate migratory] patterns may evolve and should stimulate some good discussion among students of migration ecology.”

PHYSICS

Magnetic Fields Give Heat a Curious Sideways Shove

Adrian Cho

Heat flows straight from a hot spot to cold one, right? Not always, says a group of physicists in France: A magnetic field can push heat sideways, skewing its path. The odd phenomenon mimics a piece of basic physics known as the “Hall effect,” in which a magnetic field exerts a sideways force on flowing electric current. But researchers aren't sure how a magnetic field diverts heat. “I cannot find fault [with the observation], but I cannot find an explanation,” says experimenter Anthony Kent of the University of Nottingham, U.K.

Cockeyed.

Heat usually flows straight from the hot end (red) to the cold end (blue) of a bar (left). But a magnetic field skews the flow.

CREDIT: ILLUSTRATION: C. BICKEL/SCIENCE

In 1879, American physicist Edwin Hall studied the flow of current along a rectangular conductor from one end to the other. He discovered that when he directed a magnetic field through the bar, a voltage difference appeared from one side to the other, perpendicular to the current. That happens because the electrically charged electrons feel a sideways “Lorentz force” as they travel across the magnetic field. So they accumulate along one edge of the conductor, producing the voltage.

Now, Geert Rikken of the National Pulsed Magnetic Field Laboratory in Toulouse, France, and Cornelius Strohm and Peter Wyder of the Grenoble High Magnetic Field Laboratory in France have shown that a magnetic field can affect heat flow in much the same way. They cooled a small bar of terbium gallium garnet, an electrically nonconducting material used in laser optics, to 5 kelvin and used a heater to make one end 1 kelvin hotter than the other, as they report in the 7 October issue of Physical Review Letters. The researchers applied a hefty magnetic field of a few tesla perpendicular to the bar and observed a temperature difference of about a ten-thousandth of a kelvin from one side to the other. That showed that the field had forced heat to flow slightly to one side.

In an insulator, heat is carried not by electrons but by quantized vibrations known as “phonons.” Because phonons have no charge, they should not experience a sideways Lorentz force. That reasoning led some researchers to question the result, Rikken says. “Quite a few people refused to believe it,” he says.

But the field can affect phonons indirectly when they scatter off the magnetic terbium ions. The phonons can be thought of as spiraling oscillations twisting clockwise or counterclockwise relative to the direction they're traveling. Rikken and colleagues argue that in a magnetic field, phonons with opposite twists travel at unequal speeds and scatter in different directions at different rates. That leads to a net flow of phonons to one side of the bar, they say.

Kent has some doubts about that explanation. “I'm trying to think where the difference in speed comes from,” he says. But James Wolfe, an experimenter at the University of Illinois, Urbana-Champaign, says the observation itself is convincing. “It evokes a 'Wait a minute …' response,” he says, which should spur theorists to puzzle through the essential details.

METEOROLOGY

Rise of the Forecasting Machines

Richard Kerr

For almost half a century, human and computer have been vying to predict the weather better. The computer long ago won the race to forecast out to a week and beyond, and human forecasters began giving ground at shorter ranges. Now comes evidence that computer simulations—aided by automatic statistical analysis—can consistently best humans at forecasts longer than 24 hours. The finding heralds an age of prognostication untouched by humans.

The latest from the forecasting wars comes in a paper soon to be published in the Bulletin of the American Meteorological Society. Meteorologists Jeffrey Baars and Clifford Mass of the University of Washington, Seattle, examined machine-generated forecasts of weather at 29 locations throughout the United States during a recent year and compared them with the routine predictions made by forecasters at the National Weather Service (NWS).

The machine forecasts begin with model simulations of the coming weather across the United States. These are generated at NWS's National Centers for Environmental Prediction in Camp Springs, Maryland, from weather observations collected in the preceding few hours. Then, a purely statistical analysis corrects the model forecast, basing its adjustments on comparisons of how well past model forecasts matched reality.

The human factor.

Forecasters can consistently improve computer forecasts (here, precipitation), but only through the first day ahead.

That approach, known as Model Output Statistics (MOS, pronounced “moss”), can correct any errors the model makes consistently, such as calling for too much warmth or rain or wind. It can also take into account the effects of features too small to show up in the model, such as mountainous terrain. A MOS forecast forms a baseline that forecasters from NWS, as well as private companies and TV stations, try to improve upon, using their knowledge of meteorology and lingering model shortcomings that MOS cannot correct. The Baars and Mass study suggests that by continually improving machine forecasts, human forecasters are putting themselves out of work. “For all but the first 12-hour [forecast],” they write, “it is very difficult for forecasters to consistently beat MOS.”

In most cases, Mass and Baars argue, human forecasters should spend most of their time on the first 12 hours or so. The rest of their time could be spent making sure the model and MOS are not making any blunders at longer ranges. Michel Béland, a director at the Meteorological Services of Canada in Dorval, Quebec, says that Canadian forecasters have already pulled back. They now primarily focus on severe and high-impact weather expected over the next 18 hours. Beyond that, the machines stand watch.

PLANETARY SCIENCE

Titan Clouds Hint of Heavy Rains, Methane Gurglings

Richard A. Kerr

Astronomers monitoring Titan from Earth and planetary scientists watching it from the passing Cassini spacecraft are reporting some funny business on Saturn's giant moon. Titan's rare clouds pop up in midlatitudes like smoke from a chimney, they say, and then rain out their methane as they blow downwind. But these midlatitude clouds appear over just a few small spots. That suggests that there's something special about the surface beneath them, possibly the presence of erupting methane volcanoes or geysers.

As they report on page 474, planetary scientist Caitlin Griffith of the University of Arizona (UA), Tucson, and her teammates on Cassini's Visual and Infrared Mapping Spectrometer (VIMS) watched the four clouds visible last 15 January as Cassini approached Titan. Within a narrow range of wavelengths in the near-infrared, VIMS could make out small cores to the clouds where plumes rose as fast as 36 kilometers per hour, like a summer afternoon's thunderhead. “They're probably convective, and vigorously so,” says Griffith. On reaching altitudes as high as 42 kilometers, some clouds then fell 10 kilometers in an hour as they blew downwind to the east.

On track.

Titan clouds tend to form in a line at mid southern latitudes, perhaps over methane eruptions. They are imaged here in the infrared from Earth (top) and by the Cassini spacecraft (bottom).

To fall that fast, those clouds must have consisted of millimeter-size raindrops of liquid methane, the VIMS team says. Planetary scientist Ralph Lorenz of UA and colleagues showed early this year that Titan's lower atmosphere—loaded with methane but starved of heat energy by the distant sun and enshrouding haze—should produce such rare but intense convection. Methane rain probably reaches the surface from the kinds of clouds they saw, says Griffith. That would help explain the heavily eroded icy terrains seen through Cassini's Huygens probe (Science, 21 January, p. 330).

Astronomer Henry Roe of the California Institute of Technology in Pasadena and his colleagues had a far more distant observing perch at the Keck and Gemini observatories on Hawaii's Mauna Kea, but they were able to monitor Titan much longer. On page 477, they report spotting 24 clouds over 82 nights of observing. The abundance of examples enabled them to confirm that Titan clouds outside the south polar region—at least the larger ones they could detect—form almost exclusively near 40°S latitude.

Griffith and her colleagues see the same latitudinal preference. That's because the atmosphere's larger-scale circulation boosts rising plumes there, they say. Theory and modeling by others suggest that the moon's south-flowing near-surface winds rise near 40°S in the current southern-hemisphere summer. That would encourage convection at that latitude, they note.

Roe and colleagues are more intrigued by another geographic preference of Titan's clouds. They found that three-quarters of their clouds appeared in one-quarter of the circumference of the 40°S latitudinal band. The clustering was centered at a longitude of 350°W. The other quarter of the observed clouds fell in a broader band just to the west, and the rest of 40°S had no detectable clouds. Everyone assumes that there's something different about the surface beneath the clouds—on Earth it might be a mountainous obstacle or a sun-warmed coast—that promotes towering plumes of rising air. On Titan, the clouds' longitudinal preference “is pretty much still a mystery,” says Griffith.

Roe and his colleagues don't have an answer either, but they have ruled out some possibilities. Over time, the clouds appear in slightly different places within their preferred band, Roe notes, which argues against inevitably stationary mountains as triggers. And 40°S clouds come and go too quickly to be fueled by higher summertime solar heating. That leaves geysering or the volcanic eruption of methane from the icy interior, says Roe. The methane added to the atmosphere could destabilize it and trigger a rising plume, he says. Cassini has found signs of such “cryovolcanism” in icy lava flows and volcanolike edifices (Science, 8 April, p. 193) but no definite signs of ongoing activity—at least, not yet.

TOXICOLOGY

Panel Finds No Proof That Phthalates Harm Infant Reproductive Systems

Jocelyn Kaiser

An expert panel convened by the U.S. government has thrown cold water on a widely publicized study suggesting that hormonelike chemicals in consumer products are warping the reproductive systems of baby boys. Although animal studies raise concern about infants' exposure to these chemicals, known as phthalates, there is no solid human evidence that they are harming babies, the panel concluded last week after a 2.5-day meeting. “The data are insufficient,” the panel's report states.

The phthalate review, organized by the National Toxicology Program (NTP), puts the burden of proof back on those who attribute harm to these so-called endocrine disrupters, humanmade chemicals that can act like hormones. Phthalates are found in everything from nail polish to plastic PVC plumbing. In studies with rats, high doses of phthalates act as antiandrogens, blocking the effects of testosterone, and can cause problems such as undescended testicles in male pups exposed in the womb. These findings led a 2000 NTP panel to express “concern” about possible exposures to the most common phthalate, DEHP, in healthy infants and “serious concern” about potential effects on very sick infants, who can be exposed to relatively high levels leaking from medical tubing and blood-storage bags. Such worries have already led Europe to ban certain phthalates from cosmetics and baby toys, and some companies are voluntarily removing DEHP from medical products.

Vulnerable.

Babies undergoing medical procedures may be at risk of effects from hormonelike chemicals called phthalates.

CREDIT: STEWART COHEN/GETTY IMAGES

In May, an explosive report seemed to confirm these fears, providing evidence that phthalates were subtly affecting sexual development in infants. In the online Environmental Health Perspectives, epidemiologist Shanna Swan of the University of Rochester, New York, and colleagues reported that in a study of 85 boy babies, those whose mothers were exposed during pregnancy to higher levels of four phthalate metabolites echoed a pattern seen in phthalate-exposed rat pups: The boys overall had a shorter anogenital distance (AGD)—the space between the anus and genitalia—and were more likely to have smaller genitals and partially descended testicles. Swan also found a less-than-significant association between shorter AGD and two DEHP metabolites. The Swan study made a huge splash in the press, most recently on the front page of the Wall Street Journal.

But the panel, 11 scientists charged to look at a wave of new research on reproductive risks of DEHP, found Swan's results inconclusive. Pointing to the lack of a significant association with DEHP metabolites, it notes that Swan's AGD measure is a “novel index” whose relevance in humans “has not been established.” Two toxicologists on the panel questioned Swan's data on other phthalates as well. One of the strongest associations with AGD shortening was found with a compound that doesn't cause comparable effects in animals, says Kim Boekelheide of Brown University in Providence, Rhode Island. “It makes everybody scratch their head” and wonder, “Is this just noise?” adds Robert Chapin of Pfizer.

The NTP panel also found that the small number of subjects and possible confounding factors limited the usefulness of several other new human studies, including one linking higher phthalate exposure and lower testosterone levels in infant boys. The panel's conclusion: There is “insufficient evidence in humans” that DEHP exposure during pregnancy, childhood, or adulthood is causing harm. Swan says she's not surprised that the panel dismissed her report because its focus was DEHP, and her data finding an effect for that particular phthalate were only “suggestive.” She defends her results for other phthalates, saying humans may respond differently than rats do to some of these chemicals.

The NTP panel did feel that Swan's study broke new ground: It recommends repeating the work with a larger sample size. Swan says she's in the middle of that. Boekelheide says others too will be looking at AGD, which he calls an “exciting” potential measure of endocrine effects in babies. “It's the kind of study we need to have more of,” he says.

NATIONAL INSTITUTES OF HEALTH

NIH Aims to Create 'Homes' for Clinical Science

Jocelyn Kaiser

Elias Zerhouni's mantra since taking the helm of the National Institutes of Health (NIH) 3 years ago has been “translational research”—meaning he wants to find better ways to move basic discoveries into the clinic. Last week, Zerhouni unveiled perhaps his most radical proposal yet for achieving that goal. As he explained in a commentary in the 13 October New England Journal of Medicine, NIH plans to create academic “homes” for clinical and translational science over the next 7 years and establish “a new … academic discipline.”

Research institutions are reacting with both excitement and anxiety. “It's really long overdue,” says William Crowley, director of clinical research at Harvard's Massachusetts General Hospital in Boston. One worry, however, is that by mandating such medically oriented homes, NIH will force institutions to wall off clinical researchers instead of bringing them together with basic scientists. “The danger is separatism. Most people believe clinical and translational research should be part of the fabric of the whole institution,” says Howard Dickler, director of the research division of the Association of American Medical Colleges.

NIH says inclusion is the goal of the new plan, part of Zerhouni's Roadmap, initiatives that pool money from all 27 NIH institutes and centers for common projects. The problem it addresses, notes Crowley, is that there are too few new clinical scientists in academia; many find research less appealing than other careers. The genomics explosion and rise in chronic disease, Zerhouni adds, require individualized treatments that move from bench to bedside “in a much more facile way.”

NIH's solution is to restructure the 74 institutions that now have NIH-funded General Clinical Research Centers (GCRCs), units with beds for clinical research. Each institution will have to merge its GCRC, clinical research training, and resources such as biostatisticians, regulatory staff, and safety review boards into a new, more efficient “home.” The homes will incorporate other translational research, such as animal testing and designing clinical trials. The final entity—a center, department, or institute—will award graduate and postgraduate degrees in clinical research and related disciplines. And the director must have some authority for hiring and promoting faculty, which NIH hopes will make clinical research a more attractive career path.

In 2006, NIH will spend $30 million on four to seven of these Clinical and Translational Science Awards (CTSAs),* which will supplant the recipient's GCRC. Another $11.5 million will go for planning grants up to 50 other institutions. All institutions with GCRCs will have to compete for a CTSA by 2012, when funding will total $500 million. About 60 CTSAs will be funded, fewer than the current 78 GCRCs.

At least one school, the University of Texas Southwestern Medical Center in Dallas, has already created a department of clinical research. Others are wary. It's “a huge deal” to set up a department, says Judith Swain of the University of California, San Diego (UCSD), and “it just silos clinical research.” Instead, UCSD wants to keep clinical scientists in their present departments but give them joint appointments in the clinical home. Some institutions, such as the University of Kentucky (UK) in Lexington, are also putting clinical and basic scientists in groups focused on a disease process or problem, such as atherosclerosis. “It forces people to think differently,” says UK research dean William Balke.

Although the program will be “flexible,” says National Center for Research Resources acting director Barbara Alving, medical school leaders aren't yet clear on how to meet NIH's requirements. Many are also nervous about where the funds will come from at a time when NIH's budget is likely to be flat at best. NIH says it will not cut individual investigator-initiated grants to fund the CTSAs but will draw on Roadmap funds and existing clinical and translational programs. As always, says Dickler, “the devil is in the details.”

Panel Calls for More Science Funding to Preserve U.S. Prestige

Eli Kintisch

Last week, a National Academies panel delivered a dire warning to Congress: Give science an extra $10 billion annually, or watch jobs and national status disappear to Asia. Many people may agree with the message, but details of the panel's ambitious prescriptions are already drawing criticism.

Tasked by Congress in May to assess U.S. technical competitiveness and offer recommendations to sustain or improve it, the 20-person panel included Nobel laureates and high-tech CEOs. Its report* found that U.S. scientific dominance is eroding. The worrisome indicators include a rapidly expanding Asian technical base, subpar U.S. precollege science and math education, and a U.S. shift away from fundamental research. “[A] frog that is heated slowly until it boils won't respond until it is too late,” the committee explained in its report, Rising Above the Gathering Storm.

The group proposed new $20,000 college scholarships for students who commit to teaching science in public high schools and recommended expanding programs for graduate students in needed fields, including a quadrupling of current federal early-career awards. It further called for an eventual doubling of the $8 billion the United States currently spends on basic research in the physical sciences each year. And to encourage industrial research, the group proposed reforming the patent system, expanding visa programs for foreign scientists, and making permanent an expanded R&D tax credit. “We cannot afford not to [invest],” says panel chair and former Lockheed Martin CEO Norman Augustine.

The panel's sweeping recommendations may face a tough reception. The congressional Government Accountability Office reported last week that little is known about the effectiveness of current federal scholarship programs totaling $2.8 billion. And some science education experts worry that the higher education recommendations could create a glut of scientists. “There hasn't been a huge increase in the amount of biomedical scientists as the NIH [National Institutes of Health] budget has doubled,” notes demographer Michael Teitelbaum of the Alfred P. Sloan Foundation in New York City.

Lesson plan.

An academies' report calls for funding more science teachers and extra money for physical sciences.

Massive new federal investment in basic research would, counters retired Merck chair and panel member Roy Vagelos, “invent new industries.” Those emerging fields, in turn, will create a “continuing wave of new jobs,” says Association of American Universities president Nils Hasselmo. While acknowledging that the U.S. government spends more on R&D than the rest of the G7 industrialized nations combined, the report says that federal funding for the physical sciences has been flat in 2005 dollars since the 1970s. It calls for a new “small, agile” research agency within the Department of Energy akin to the Defense Advanced Research Projects Agency.

House Science Committee staff director David Goldston says that proposal ignores the fact that promising energy technologies are currently available but underutilized. “There might be much more of a deployment problem than an R&D problem,” he says. Others question the broader call for a federal research boost. “We need a more precise policy than simply spending more money,” says science policy specialist David Guston of Arizona State University in Tempe.

Panelists acknowledge that high-level groups have made sweeping calls like this before, with little effect. Given that science budgets are expected to stay flat or face small cuts in 2006, Guston and other policy watchers say they are skeptical that the report's call for billions in new funding will fly. Still, Senator Lamar Alexander (R-TN), who had called for the panel, says its proposals could garner support from many lawmakers who are concerned about U.S. jobs, especially if the White House endorses the report. “Now it needs the imprimatur of the president,” he says. A White House spokesperson says the president welcomes the new report.

You Make the Call, NASA Chief Tells Scientists

Carolyn Gramling,

Andrew Lawler

Faced with problems fixing the space shuttle, finishing the international space station, and winning support for an ambitious exploration effort, NASA Administrator Michael Griffin told researchers last week that he was “fed up” with conflicting advice from the science community. Instead of expecting more funds, Griffin explained to the federal Astronomy and Astrophysics Advisory Committee, researchers need to make tough choices about how to spend what money is available.

Tough talk.

Michael Griffin wants scientists to figure out how best to spend NASA's shrinking science budget.

CREDIT: CRAIG BAILEY/AP PHOTO

The NASA chief's blunt talk comes as he and the White House negotiate the agency's 2007 budget request, which will be released in February. Science accounts for nearly a third of NASA's $16 billion budget, which is unlikely to increase faster than inflation in coming years—and neither is science's share of it, Administration officials say. “The good news is that the NASA administrator is going to give us our fair share,” says Lennard Fisk, a solar physicist at the University of Michigan, Ann Arbor, and chair of the National Academies' Space Studies Board. “The bad news is that … we can't execute the programs we have with the money available.”

The community's intense—and successful—lobbying to repair the Hubble Space Telescope is a good example of how a sound scientific argument can conflict with a limited budget, Griffin told the advisory panel, which was formed 2 years ago to coordinate space and ground-based astronomy funded by NASA, the National Science Foundation, and the Department of Energy. “The astronomy community did this to itself,” he said. Unless the James Webb Space Telescope—currently $1.5 billion over budget—is scaled back, he warned, “I just don't see how to pay for other missions.”

Researchers say they are willing to make those choices, but they note that NASA has disbanded its own advisory council. The agency has not sought advice yet from the academy panel on how to manage its fiscal crisis and avoid a civil war among disciplines fighting for limited resources.

“How to give the advice is not clear,” says Fisk. He notes that the NASA panel has been in limbo since Griffin arrived in March. The administrator is expected to make sweeping changes to the council's membership, including replacing chair Charles Kennel, an earth scientist and head of Scripps Institution of Oceanography in San Diego, California. Fisk adds that the academies' board is willing to lend a hand on setting scientific priorities if NASA asks.

Griffin reiterated his intention not to divert science funding to other areas within his agency, and his direct approach resonated with some federal advisory panel members. “Mike does listen to people,” says chair Garth Illingworth, an astronomer at the University of California, Santa Cruz, adding that he was reassured by Griffin's invitation to astronomers to step up to the plate. “If the previous administrator had involved the community in the decision” to cut the planned Hubble mission, he notes, the astronomy community could have evaluated its choices more carefully before deciding to lobby legislators to save Hubble.

“We're all dealing with the collateral damage from inappropriate methods of thinking,” said Griffin. On that point, adds Illingworth, “I couldn't agree more.”

SCIENTIFIC PUBLISHING

Retracted Papers Spur Million-Dollar Lawsuit

John Travis

One of the authors of two plant biology papers that were retracted last year is suing the senior author who withdrew the papers. She is alleging that her former lab chief threatened to ruin her career and then did so with the retractions.

In notices published almost a year ago, Daniel Klessig of the Boyce Thompson Institute (BTI) for Plant Research in Ithaca, New York, and several colleagues said they were retracting two papers, which described a new plant enzyme and had appeared in Cell and the Proceedings of the National Academy of Sciences (PNAS), because they had been unable to reproduce certain results. The retraction notices, however, were not approved or signed by the first author on both papers, Meena Chandok (Science, 5 November 2004, p. 960).

Chandok has now launched a legal counterattack. In late August, she filed a civil lawsuit in a U.S. district court in Syracuse, New York, seeking more than $1 million in punitive and compensatory damages from Klessig. (BTI, Cell, and PNAS were not named as co-defendants.) The lawsuit, which was first reported by The Scientist, states that Klessig had falsely leveled misconduct charges—including that Chandok fabricated data in the papers—and that a BTI investigation did not validate those allegations. In a 14 July memo to Klessig and Chandok, provided to Science by Chandok's lawyer, BTI president David Stern confirms that an investigation had not substantiated the charges but adds: “There are numerous disputes on factual issues and divergent viewpoints that I cannot or will not attempt to resolve or reconcile.”

Among other claims in her lawsuit, Chandok alleges that after she resigned from the lab in March 2004, Klessig threatened to press misconduct charges and withhold support for her visa-extension application if she didn't help him with further research on the enzyme. “As a result of the false allegations, Dr. Chandok's reputation has been damaged in the scientific community,” the suit states.

Klessig denies Chandok's charges. He told Science: “Because we were unable both to reproduce the critical data … and to verify certain biological reagents used in the original publication, I was ethically compelled to retract the papers.” No trial date has yet been set.

AVIAN INFLUENZA

Are Wild Birds to Blame?

Dennis Normile

As H5N1 reaches Europe, scientists debate the role of wild birds but agree on the need for greater surveillance

Almost as soon as H5N1 avian influenza began its deadly sweep across Asia, people fingered migratory birds as likely culprits in its spread. Migrating birds offer an obvious way to connect the dots of H5N1 outbreaks along the east coast of Asia and, in just the past few months, its unexpected cross-continent jump to Siberia, Kazakhstan, and Turkey. Moreover, researchers have long known that these birds commonly harbor less virulent flu viruses, and many wild birds mingle with Asia's free-ranging domestic poultry, which have been decimated by H5N1.

But avian experts have been almost universally skeptical that wild birds are spreading the virus. One reason is that sampling of tens of thousands of birds has failed to turn up a single healthy wild bird carrying the pathogenic strain of H5N1, which has caused the death of more than 100 million domestic birds—and at least 60 humans—in Asia. Evidence so far suggests that H5N1 kills wild ducks and geese nearly as efficiently as it does chickens. “Dead ducks don't fly” has been the refrain, as avian experts point out that sick and dying birds simply can't spread viruses very far. Instead, epidemiologists investigating the virus's jump, even to geographically far-flung regions, keep turning up evidence suggesting that the poultry trade and other human activities are responsible.

Now, however, evidence implicating wild birds is starting to convince even some of the doubters. “Until about 2 months ago, I was pretty skeptical on whether wild birds were playing a role,” says David Suarez, a virologist with the U.S. Department of Agriculture's (USDA's) Southeast Poultry Research Laboratory in Athens, Georgia. “But now I feel that there is much stronger evidence that wild birds are spreading the virus.” What changed his mind, he says, was the death of 100 or so ducks, gulls, geese, and swans from H5N1 at a remote lake in Mongolia that he believes can't be explained by human activities. And, he and others add, in an unexpected twist, it's beginning to look as though the culprits might not be the long-suspected migratory waterfowl but another yet-unidentified wild species.

The implications are huge. If wild birds are carrying the disease, says Suarez, “it will be difficult or impossible to control the spread from country to country.” Nailing down the answer became even more urgent last week with the confirmation that H5N1 has now entered Europe.

Heads up.

Researchers worry that bar-headed geese might carry the H5N1 virus from the sites of outbreaks in northern China and Mongolia to India and Bangladesh.

CREDIT: WILLIAM B. KARESH/WILDLIFE CONSERVATION SOCIETY

Even before that confirmation, the Netherlands ordered farms along migratory routes to keep poultry inside, and three German states asked farmers to voluntarily take similar precautions. Last month, the European Commission rejected proposals to extend such measures throughout the union, but E.U. officials were reassessing their stance with the news that H5N1 has reached Turkey (see p. 417). Everyone recognizes that if wild birds are involved, new strategies will be needed to halt the virus's spread to domestic flocks—and from them to people. A growing number of scientists and organizations are calling for dramatically increased global surveillance to profile all viruses circulating in wild birds. Says Kennedy Shortridge, a virologist and professor emeritus at the University of Hong Kong, “H5N1 is important, but we still need to be on the lookout for other flu viruses.” The costs of surveillance are small, he says, considering the damage that could be done to the poultry industry—or, worse, the potential for a human pandemic.

From low to high

One reason migratory waterfowl were high on the list of suspects for spreading H5N1 is because they are natural hosts for other bird flu viruses. But Ilaria Capua, a virologist at Italy's National Reference Laboratory for Avian Influenza in Padua, warns that Anatidae, the family that includes ducks and geese, are as genetically distant from gallinaceous birds (chickens, turkeys, and quail) as cats are from dogs. The different families interact with viruses very differently, she says.

Viruses are subtyped by the forms of two of their surface glycoproteins, hemagglutinin (H) and neuraminidase (N). There are 16 forms of hemagglutinin and nine of neuraminidase. Viruses are further classified as being of low or high pathogenicity. Low-pathogenicity viruses are typically carried in a bird's intestinal and respiratory tracts and usually cause mild or no symptoms. Highly pathogenic viruses can infect cells throughout a bird's body and cause systemic disease and, usually, death.

Waterfowl have been shown to carry low-pathogenicity viruses of virtually all possible combinations of H and N, including low-pathogenicity versions of H5N1. So far, however, there is no known natural reservoir for highly pathogenic avian influenza viruses. They emerge only after low-pathogenicity viruses jump from water birds into chickens and turkeys. As the virus attempts to adapt to a new host, it somehow acquires the ability to infect cells throughout the bird's entire body. This mutation from low to high pathogenicity, with a resulting bird flu epidemic among poultry, has occurred at least 19 times since 1959. In some cases, researchers have traced the virus from its low-pathogenicity form in water birds to a low-pathogenicity virus that circulated in poultry before becoming highly pathogenic.

No one has yet uncovered the lineage of the highly pathogenic H5N1 strain now endemic in Asia. Presumably, it evolved from a low-pathogenicity H5N1 variant circulating in waterfowl in southern China before the first known outbreak of the disease in chickens in Hong Kong in 1997. By culling all 1.5 million domestic poultry in Hong Kong, authorities stamped out the outbreak. With a few exceptions, the virus was not seen again until December 2003, when a massive outbreak swept chicken farms in Korea. By January, the virus had turned up on farms in Japan and Vietnam; by February it was detected in Indonesia, and it was soon killing chickens in Thailand and China.

When public health experts pointed to migratory birds as a likely source, ornithologists and animal epidemiologists showed that the outbreaks did not neatly fit any known migratory patterns. If migratory birds were carriers, they argued, the virus should have turned up in the Philippines and Taiwan by now, but it hasn't. What's more, since the late 1990s, USDA has sampled more than 10,000 waterfowl crossing the Bering Sea from Asia to Alaska, while University of Hong Kong researchers have tested several thousand entering Hong Kong; neither group has found a single healthy bird carrying the H5N1 virus.

On the fly.

Flyways might seem to connect the dots of H5N1 outbreaks, but the timings and locations aren't a perfect fit with known migratory patterns.

CREDIT: FLYWAYS: WETLANDS INTERNATIONAL

Instead, human movements of infected poultry have spread the virus over seemingly improbable distances. For instance, an outbreak of H5N1 among poultry in Lhasa, Tibet, in January 2004 was traced to a shipment of chickens from Lanzhou in China's Gansu Province, about 1500 kilometers away. An even more bizarre case surfaced in October 2004, when an air traveler was caught at Brussels Airport with two crested hawk eagles, infected with H5N1, in his carry-on bag. The smuggler had bought them at a Bangkok bird market on behalf of a Belgian falconer.

A new paradigm

As the epidemic continues, it's becoming increasingly clear that H5N1 represents a “change in the paradigm” of what is known about avian influenza viruses, says Les Sims, a veterinarian in Manunda, Australia. Before this strain of H5N1 appeared, for instance, waterfowl were thought to be resistant to infection by highly pathogenic viruses. Studies over the last several years have shown that domestic ducks can asymptomatically carry some strains of H5N1 that are lethal to chickens. (Yet other H5N1 strains are lethal to domestic ducks.)

Until last spring, however, there was no sign that H5N1 was infecting any wild birds in a significant way. That changed in April, when an H5N1 outbreak at Lake Qinghai in northwestern China killed an estimated 5000 to 6000 migratory water birds.

The die-off immediately raised alarms that surviving birds might carry the virus to India and beyond. But, apparently because of infighting between Chinese ministries and institutions, the government barred Chinese and outside scientists from sampling or tracking the travel of surviving birds. “It was a missed opportunity,” says ornithologist David Melville from Nelson, New Zealand.

Stowaways.

These crested hawk eagles, infected with H5N1, were smuggled from Bangkok to Brussels in an air traveler's carry-on bag.

Researchers are still wondering how the virus got to this remote corner of China. Just after the Lake Qinghai outbreak, the virus turned up on a poultry farm in the same province. This “makes it difficult to tell whether poultry or wild birds brought the virus to the area,” says Suarez.

An August outbreak at Erkhel Lake in Mongolia, however, helped persuade Sims that wild birds are to blame, but his change of mind comes not from finding a positive link but from ruling out human movements of poultry, he warns. “All epidemiology is based on probabilities,” he adds.

A group of veterinarians from the Wildlife Conservation Society was already in Mongolia in case H5N1 made the 600-kilometer leap when it heard of unusual bird deaths at Erkhel Lake. The group collected 774 samples from both dead and living birds. USDA confirmed highly pathogenic H5N1 in dead birds—but found no evidence of the virus in any samples from the live ducks, gulls, geese, or swans.

Because there are so few poultry in this isolated region, Suarez thinks their involvement is “unlikely.” “The most likely scenario,” he says, is that wild birds carried the virus to Erkhel Lake and infected the birds that eventually died. “We don't know which species were responsible for spreading the virus,” says Sims, who is also involved in the project, although he suspects that those unidentified species could be spreading the virus elsewhere. (The researchers declined to provide further details because they are readying an article for publication.) Figuring out which species might be involved will be tough, others note, as next to nothing is known about avian influenza except in waterfowl.

Searching

Some answers may come from Fu-Min Lei, an ornithologist at the Institute of Zoology in Beijing, part of the Chinese Academy of Sciences (CAS). Since last March, he has collected more than 6000 viral and serological samples from a variety of wild animals throughout China, including 2000 samples from migratory and resident birds, and is searching for H5N1.

Another Chinese team led by George Gao, a virologist at CAS's Institute of Microbiology in Beijing, has collected several dozen serum samples from birds that survived the H5N1 outbreak at Qinghai Lake. If any test positive for antibodies to the H5N1 virus, says Gao, who is preparing to publish a paper, it would suggest that some mildly infected water birds might be carrying the virus long distances.

Even before the virus turned up in Turkey, the incidents at Qinghai and Erkhel and the spread of the H5N1 virus through Siberia and Kazakhstan had sparked new surveillance efforts. In Europe, Albert Osterhaus, a virologist at Erasmus University in Rotterdam, the Netherlands, has proposed a Europe-wide wild bird surveillance program. His group currently gathers cloacal samples from 6000 birds annually, primarily in the Netherlands (see sidebar). Extending such surveillance to critical migratory routes crossing Europe, which he estimates would cost about $2.5 million, would not only serve as an early warning system for a possible pandemic, he says, but also provide data on other viruses that pose a threat to domestic flocks. Osterhaus would like to see similar networks set up to cover flyways in Asia-Pacific and the Americas.

Other nations have not recognized the need, so surveillance is patchy, except in Asia, which has an aggressive program of sampling wild birds and birds brought to live poultry markets.

The United Nations Food and Agriculture Organization (FAO) is helping nascent surveillance efforts in South Asia, and the World Organisation for Animal Health recently sent an expert mission to support surveillance in Russia. “We're very concerned about India and Bangladesh,” says FAO's Juan Lubroth, because the bar-headed geese that breed at China's Qinghai Lake winter in South Asia. But Lubroth notes that wild bird surveillance is just one on a long list of veterinary needs that includes strengthening local lab capabilities and improving hygiene on farms and in markets. All these measures are desirable no matter how H5N1 is being spread, he says. FAO has appealed to the international community for $100 million to fight avian influenza in Asia but has so far only raised $30 million—a small sum, Lubroth says, for trying to avert a human pandemic.

AVIAN INFLUENZA

Keeping Track of Viral Air Traffic

Martin Enserink

BERKENWOUDE, THE NETHERLANDS—Catching wild ducks, an art that requires skill as well as patience, has a long tradition in this water-rich country. But these days, Dutch duck trappers are helping address a 21st century challenge by taking stock of the dizzying variety of bird flu strains flying overhead—and perhaps providing early warning should the fatal H5N1 strain arrive. At Erasmus Medical Center in Rotterdam, virologist Vincent Munster runs one of the largest surveillance programs for avian influenza in the world, and he relies on dozens of people who catch birds, either for a living or as a hobby, to send him more than 8000 samples a year.

Bert Pellegrom, a forester whose hobby is keeping a 200-year-old duck trap operational, is one of them. At his trap—really a small lake, surrounded by reed screens to hide the trapper from the birds and equipped with elaborate netting structures—Pellegrom catches ducks several times a week, which he kills and sells to the local poulterer. (They fetch about $4 a bird.) On a sunny afternoon last week, conditions weren't favorable—too warm and not enough wind—but Pellegrom caught two mallards. “This may look a bit unpleasant,” he cautioned, before wringing their necks. Then he got some sterile cotton swabs from a shed, inserted one in each of the ducks' cloacas, and turned it around once before pulling it out and storing it in a small plastic bag.

Between 1% and 20% of all ducks, depending on the species and season, are infected with an influenza strain, usually without symptoms, Munster says. Back at the lab, he and his colleagues culture viruses from the samples, determine the strain, sequence the signature hemagglutinin gene, and check whether they have low or high pathogenicity. Although duck trappers like Pellegrom supply some of the samples, the majority come from ornithologists—in the Netherlands, Sweden, and far-flung places such as Japan, Canada, and South America—who ring wild birds for migration studies and release them. Together, the samples cover hundreds of different bird species, mostly ducks, geese, gulls, and shorebirds. Bit by bit, the Rotterdam group, led by Ron Fouchier, is assembling a detailed picture of which viral strains are out there, which bird species each strain prefers to infect, and how patterns change with the seasons.

Helping hands.

Bert Pellegrom (right) is one of many people collecting samples for the avian influenza surveillance program run by Vincent Munster.

CREDIT: M. ENSERINK/SCIENCE

When the program started 5 years ago, it was a leisurely academic endeavor, and the researchers analyzed the samples only after the end of each migration season. But after H5N1 started its path of devastation from China to Turkey, the group realized that it offered a possible early warning system as well. Two months ago, they started collecting samples weekly and screening them as soon as they come in. If highly pathogenic H5N1 makes it to northern Europe, Munster hopes he will be the first to know. The group has applied for European Union funds to expand the network across Europe.

Munster rarely goes on field trips himself. But when he accompanied a reporter to Pellegrom's trap, his study produced an unexpected benefit: Rather than selling them, Pellegrom offered the two birds to Munster, who, for the first time in his life, got to carve up, roast, and eat his research subjects at home.

AVIAN INFLUENZA

Preaching Against the Pandemic

Martin Enserink

He's a retired American living in the French countryside. So what makes David Fedson one of the most vocal advocates for pandemic preparedness?

SERGY HAUT, FRANCE—On a clear day, you can see Mont Blanc, Europe's highest mountain, from David Fedson's study. His 320-year-old home, tastefully restored and decorated, is a haven of tranquility in a small French village.

But the relaxed atmosphere is deceptive. Working from his home, Fedson, 67, a former academic and pharma executive, is on a tireless crusade to help ready the world for what he believes could be a global catastrophe: the next influenza pandemic. After a career spent studying adult vaccination, he's convinced that only billions of flu shots, deployed worldwide soon after a pandemic strikes, could avert global mayhem. And the world still isn't moving fast enough to make that possible, he says.

To change that, Fedson is constantly writing papers, talking to scientists, and lobbying policymakers. Colleagues say he's an influential voice in the debate on pandemic preparedness. From 1996 until his retirement in 2002, Fedson was director of medical affairs at Aventis Pasteur MSD (now Sanofi Pasteur MSD) in Lyon. Even then, he was known to speak his mind. Sanofi Pasteur, the world's biggest flu vaccine producer, pays Fedson's expenses to speak about the pandemic danger, but he has no formal ties to this or any other company or organization, which allows him to speak freely, says Harvard epidemiologist Marc Lipsitch: “I'm kind of a fan.”

Fedson frequently tries to cajole reporters into covering the subject he worries about. In an e-mail to a New York Times reporter last year, he praised a particular story but said that overall, the paper had “barely scratched the surface,” adding, “You have work to do.”

Fedson studied medicine at Yale and worked at the University of Chicago before joining the University of Virginia School of Medicine in Charlottesville in 1982, where he became an expert in the clinical effectiveness, cost-effectiveness, and distribution of flu and pneumococcal vaccines. He was a member of the Advisory Committee on Immunization Practices and the National Vaccine Advisory Committee; at Aventis, he founded the Influenza Vaccine Supply International Task Force, an industry group working to prepare for pandemic vaccination. After retiring, he set up a study group to monitor the use of flu vaccines around the world.

Fedson's ideas about pandemic vaccines are based on simple arithmetic. In a pandemic, antiviral drugs like Tamiflu can't be more than a stopgap; only vaccines offer long-term protection. As for supply, for the next 5 years at least, the world is stuck with the nine major flu vaccine companies, which produce just 300 million doses annually using chicken eggs, a process that's difficult to scale up quickly. They could all switch to making pandemic vaccine in an emergency—but they would need to produce billions of doses instead of 300 million.

The only way to increase supply dramatically, Fedson says, is to produce vaccines that use far less antigen, or viral proteins, per dose. For the annual influenza vaccine, which protects against three different strains, manufacturers use 45 micrograms of antigen, 15 for each strain. To vaccinate 3 billion people during a pandemic—and assuming everyone will need two shots—the amount of antigen per shot would have to come down 20-fold, to about 2 micrograms. Studies have suggested that such small doses may be effective when coupled with a so-called adjuvant, such as alum, to rev up the immune system.

Work to do.

David Fedson says the world needs a global plan to develop, produce, and distribute pandemic vaccines.

CREDIT: M. ENSERINK/SCIENCE

Trials using such vaccines have been slow to start. Adjuvants aren't needed in annual flu vaccines, and they create regulatory worries about side effects. For these reasons, the first pandemiclike H5N1 vaccine that the United States tested in humans did not contain an adjuvant. The vaccine triggered reasonable levels of antibodies, but only when two doses of 90 micrograms were given (Science, 12 August, p. 996). Rather than stretch global capacity, this approach would dramatically shrink it, says Fedson. Additional trials with dose-sparing strategies, including alum, are now planned in the United States. Still, says Fedson, “they wasted a year. That's unforgivable.”

In Europe, adjuvants are widely accepted, but public funding has lagged. Sanofi Pasteur will soon complete one small study, and several more are planned. But in most studies, the lowest dose tested will be 7.5 micrograms of antigen. That's still too high, says Fedson, who recommends testing doses as low as 1.875 micrograms. The hesitation is “absurd,” he says: “We know what needs to be done, but it's not being done.”

Other hurdles need to be tackled urgently, he adds. To speed new vaccines to the market, Fedson calls for a global licensing protocol, rather than the current patchwork of national regulations. Governments should also shield companies from liability, he argues, because when large numbers of people take a vaccine, some will come down with health problems.

As an alternative strategy, Fedson has urged researchers to study patient databases to see whether statins, cholesterol-lowering drugs that also fight inflammation, might prevent the most severe complications from influenza. If so, he says, generic statins could offer poor countries a cheap alternative to Tamiflu. Two groups recently found encouraging data (Science, 23 September, p. 1976), and top flu teams in the United States have promised to test the idea in H5N1-infected mice and ferrets.

Coordinating a truly global plan for pandemic vaccine development, production, and distribution requires exceptional leadership, which Fedson says the under-funded World Health Organization in nearby Geneva can't provide. He advocates the creation of a new organization like the Global Fund to Fight AIDS, Tuberculosis, and Malaria, led by someone like the blunt and hard-driving General Leslie R. Groves, who built the Pentagon and went on to lead the Manhattan Project.

Meanwhile, Fedson has plenty of advice to give. He hands the reporter a letter urging the World Economic Forum to put the pandemic threat on the agenda of its annual elite gathering in Davos, Switzerland. (They should enlist people such as Bill Clinton, he suggests.) He produces a paper arguing for statin research and another about pandemic vaccine development. More will come by e-mail, he promises. Like General Groves, Fedson knows what needs to be done.

European Probe Returns to Our Neglected Neighbor

* Govert Schilling is an astronomy writer in Amersfoort, the Netherlands.

Venus may lack the appeal of Mars, with the possibility of life, but it has much to teach us. Venus Express is going to find out what is happening beneath the clouds

Over the past 15 years, 12 spacecraft have been launched toward Mars. In the same period, none went to Venus—even though Venus is larger, closer, and more mysterious than the Red Planet. Now the European Space Agency (ESA) is about to take a step toward evening things up. ESA's Venus Express spacecraft, scheduled for launch later this month and due to reach its destination next spring, may finally unveil some of the haze-enshrouded planet's many secrets. “In several important areas, such as atmospheric composition and variability, Venus Express will give us the best observations to date and will help us solve the puzzle that is Venus,” says astrobiologist David Grinspoon of the Southwest Research Institute in Boulder, Colorado.

Until space probes shattered the illusion, Venus was sometimes imagined as a lush, tropical paradise. Now astronomers know it is the closest place in our solar system to hell. The greenhouse effect of its thick carbon dioxide atmosphere has heated the surface to a sweltering 500°C, and its atmospheric pressure is 90 times that at Earth's surface. Sulfuric acid rains down from the planet's highaltitude clouds, while crackling lightning and possibly erupting volcanoes complete the apocalyptic scene.

Eight armored Russian landers touched down on Venus during the 1970s and 1980s, but none lasted more than a couple of hours. Because orbiting cameras can't see through the clouds, planetary scientists have had to rely on radar to study the surface. NASA's Magellan radar mapper, which operated between October 1990 and December 1994, revealed impact craters, chasms, mountain ridges, shield volcanoes, and lavalike flows. But many important facts about Venus, including its geologic and climatic history, remain a blank.

“We need to study all aspects of Venus: surface, atmosphere, interior, and how they all work together over time,” says geologist Stephen Saunders of NASA Headquarters in Washington, D.C., who was Magellan's project scientist. “Venus Express will provide many answers.” The $260 million spacecraft will focus on the venusian atmosphere, using seven science instruments, five of which are spares from two earlier ESA missions, Mars Express and the Rosetta comet chaser.

Researchers hope to peer back into the planet's past. Venus probably started out very much like Earth, but for some reason its climate went awry. And no one yet knows when clouds first shrouded the planet. “It's not clear whether or not the atmosphere of Venus is in equilibrium with the surface and the interior,” notes Jean-Loup Bertaux of France's Aeronomy Service in Verrières le Buisson, the principal investigator of one of the craft's three spectrometers. “We also want to know how much water has been around on Venus in the distant past.” Mission scientists hope to learn more about the composition and dynamics of Venus's atmosphere. Unlike the planet itself, which turns on its axis only once every 243 days, the atmosphere rotates every 4 days, creating hurricane-force winds, and an unexplained double vortex whirls above the poles.

“There are many mysteries about the clouds and the atmosphere” of Venus, Grinspoon says. For instance, an enigmatic “unknown ultraviolet absorber” high in the clouds keeps huge amounts of solar energy from reaching the surface. “We don't know what it is, but it's possible that Venus Express will help us solve this mystery.” Grinspoon thinks the clouds might even support some kind of life (Science, 29 November 2002, p. 1706). “It's an outlandish but entirely possible idea,” he says.

Researchers are also eager to find out if any of Venus's volcanoes are still active. Larry Esposito of the University of Colorado, Boulder, who works on the mission's Venus Monitoring Camera, says it's very likely that Venus is volcanically active. “It's about the same size as the Earth, so it has to get rid of the same amount of internal heat,” he says. Esposito thinks a temporary high abundance of atmospheric sulfur dioxide that NASA's Pioneer Venus Orbiter measured a quarter of a century ago could be evidence of a volcanic eruption back then. “By observing volcanic activity directly, Venus Express could settle this issue,” he says.

The team is pinning its hopes on the Venus Monitoring Camera to do this. The wide-angle camera is both an ultraviolet cloud imager and an infrared detector at about 1-micrometer wavelength, where the atmosphere is transparent. During the venusian night, the team will be able to make a temperature map of the surface, which might reveal recent lava flows, says principal investigator Wojciech Markiewicz of the Max Planck Institute for Aeronomy in Katlenburg- Lindau, Germany. The spacecraft's infrared spectrometers will also search for volcanic activity by taking accurate temperature readings of the surface. “Everybody hopes to find an active volcano on Venus,” says Markiewicz. Bertaux agrees. “There will be a friendly competition between the various instrument teams to find the first hot spot,” he says.

Lifting the veil.

Venus Express will peer through the planet's dense clouds in search of volcanic activity.

CREDIT: ESA

Right now, the biggest worry is the launch, planned for the early morning of 26 October, with a Russian Soyuz rocket and a Fregat upper stage. Orbit insertion will be the next “very critical moment,” says project scientist Håkan Svedhem of the European Space Research and Technology Centre in Noordwijk, the Netherlands. After 162 days in interplanetary space, Venus Express will settle into an extremely elongated polar orbit in which it will dip down to just 250 kilometers above Venus's surface every 24 hours. The planned mission lifetime is about 500 days, but Venus Express carries enough fuel to last twice that long.

Planetary scientists will be hoping for that and more. “Venus Express will whet our appetite for even more knowledge about our sister planet,” says Saunders.

CLIMATE CHANGE

Confronting the Bogeyman of the Climate System

Richard A. Kerr

The threat from an abrupt circulation switch in the North Atlantic and resultant climatic chaos seems to be receding, but researchers are still worried

ASPEN, COLORADO—Scientists have been warning us for a quarter-century that the climate system has some surprises up its sleeve. By the 1990s, as paleoclimatologists discovered the whiplash history of recent climate, attention turned to the far North Atlantic. There, as the world emerged from the last ice age more than 8000 years ago, the supply of warm water to high Atlantic latitudes appeared to shut down in mere decades. The collapse of the warm circulation chilled and dried surrounding lands back to near-glacial conditions for centuries, skewing regional climate around the world.

A precipitous shift in climate could happen again, say researchers, 25 of whom gathered here last summer to discuss abrupt climate change.* But the prime menace no longer lies in the North Atlantic. Instead, a growing contingent of scientists now sees the North Atlantic as no more of a threat than accelerating sea level rise, megadroughts, and monsoon failures. “A few years ago, people thought the [Atlantic circulation] could collapse almost like The Day After Tomorrow,” said paleoclimatologist Julia Hargreaves of the Frontier Research Center for Global Change in Yokohama, Japan. “But a very rapid collapse now seems fairly unlikely under global warming.”

Shifty climate

Paleoclimatologists have certainly turned up worrisome examples of abrupt North Atlantic climate change. In ice cores retrieved from the Greenland ice cap, isotopic studies showed temperature shifts of 10°C during the last ice age and during the transition out of glacial times. Projections for greenhouse warming by the end of the century are running about 1.5°C to 2°C. And other ice-core studies showed that 10° shifts took only a few years—50 at most, which is abrupt by anybody's standard.

Some of these sudden events began to look disquietingly familiar from recent events. Apparently, melting ice sheets during the last glaciation had sent meltwater gushing into the far northern North Atlantic to form a surface layer of relatively fresh and, therefore, less dense seawater. That would have thrown a monkey wrench into the far end of the ocean “conveyor belt” that carries warm surface water northward, according to the story developed by paleoceanographers. The less-dense freshwater lid would have prevented surface water from sinking at the northern end of the conveyor and returning southward. That would have jammed the conveyor and shut it down. With no added warm water from the south, the North Atlantic and surrounding land would have chilled (Science, 10 July 1998, p. 156).

Still circulating, for now.

Dumping fresh water on the far North Atlantic could, in principle, shut down the northward flow of warm surface waters (red) and the deep return of cold water (blue).

ILLUSTRATION: C. BICKEL/SCIENCE

In recent years, researchers have reported freshening seawater in the far north similar to that of the last ice age in pattern, if not in magnitude. Rivers have been dumping more fresh water into the Arctic Ocean, perhaps as the strengthening greenhouse increases high-latitude precipitation. At the same time, high-latitude Atlantic surface waters have been freshening (Science, 2 January 2004, p. 35). And at least one cog in the northbound conveyor—the subpolar gyre—has slowed of late (Science, 16 April 2004, p. 371). All the while, the conveyor circulations collapsed in one climate model after another when the North Atlantic was flooded with fresh water.

Not so simple

These discoveries commingled with the idea that humans tinkering with Earth's greenhouse could in theory drop temperatures around the North Atlantic. Some media found the result irresistible. European newspapers have carried dramatic headlines such as “Global Warming May Freeze Out British Isles,” and even the sedate National Academy Press selected Climate Crash this year as the title of a journalist-written book on abrupt climate change. And although an alarmist headline or two might not seem far out of line, some scientists are beginning to doubt that a North Atlantic shutdown is looming. Physical oceanographer Carl Wunsch of the Massachusetts Institute of Technology, for one, contends that the North Atlantic Ocean simply can't determine climate single-handedly.

Even the commonly used technical name for the conveyor is misleading, he said at the workshop. “The ocean flow is a complicated beast,” he said. Calling the ocean conveyor the thermohaline circulation (THC) has come to imply that only differences in temperature and salt content drive it. In fact, “the crucial element for knowing what the ocean is doing is knowing what the wind is doing,” he said.

His graduate school adviser, the late Henry Stommel, introduced the THC concept in 1958. But Wunsch says that Stommel included crucial driving forces such as the wind that have since been dropped. As long as the wind blows, essential parts of the THC such as the warm Gulf Stream will continue to flow, Wunsch said, “and I don't know how to stop the wind.” A safer label for the ocean conveyor might be the meridional (north-south) overturning circulation (MOC, pronounced “mock”), many at the workshop concluded.

Another complication is ice—in particular, the dearth of it around the North Atlantic. At the workshop, geophysicist Richard Peltier of the University of Toronto, Canada, argued that abrupt shifts “have something to do with ice,” noting that all of the Northern Hemisphere's glacial ice melted away shortly after the last abrupt climate event 8200 years ago. Ice might have done its work by producing fresh meltwater fast enough to put a lid on the North Atlantic. Or, as Wunsch suggests, the mountains of it sticking up into the prevailing winds at high latitudes could have skewed atmospheric circulation the way the Rockies do today. In either case, vast amounts of it seem to have been required.

Unmoved models

If the past is not a good analog for the future, computer models might serve as guides to global warming's effect on the MOC. Lately, the most sophisticated and realistic model simulations of a warmer world have failed to drive the MOC anywhere near collapse. For example, climate modeler Peter Gent of the National Center for Atmospheric Research (NCAR) in Boulder, Colorado, told the workshop how the latest version of the NCAR climate model responded to greenhouse gas increases like those expected in the next century or two. Over a range of rates of greenhouse strengthening, the model's MOC slowed by an average of 25% to 30%. “That is not a collapse,” said Gent.

Modeler Jonathan Gregory of the University of Reading, U.K., and 17 colleagues got similar results in an international comparison of models. They ran 11 different models—six of the most sophisticated sort, including an earlier version of NCAR's, and five “intermediate complexity” models—for 140 simulation years, quadrupling the concentration of greenhouse gases in the process. None led to a collapse of the MOC; instead, they slowed it gradually by 10% to 50%.

Not that model MOCs can't collapse. “If you really hit the North Atlantic with fresh water,” says Gent, “you can make it collapse.” But the flow needs to be something like 10 times faster than current greenhouse simulations, says Gent. That's also the only way to chill Europe in greenhouse models. None of the models in Gregory's inter-comparison showed a cooling anywhere; greenhouse warming always prevailed.

Not everyone is ready to consign the MOC collapse threat to the back burner, however. Climate modeler Michael Schlesinger of the University of Illinois, Urbana-Champaign, an organizer of the workshop, notes that model simulations are not entirely realistic. For one, they have yet to include meltwater from a warming Greenland. And, as geochemist Daniel Schrag of Harvard University has pointed out, models cannot yet simulate other climate extremes known from the geologic record, such as the extreme warming that occurred 55 million years ago.

By the end of the workshop, the threat of a MOC collapse seemed to have receded, at least relative to other climate threats. “The [scientific] community is way, way over-focused on the MOC,” said ice core geochemist Jeffrey Severinghaus of the Scripps Institution of Oceanography (SIO) in San Diego, California. Tropical oceanographer George Philander of Princeton University agreed: “The last 6 months, every computer center has been tied up pouring fresh water on the North Atlantic. That's not good. How do we get off this bandwagon?”

A looming MOC collapse “has inspired a Hollywood movie and a lot of fear,” said statistical economist Richard Tol of Hamburg University in Germany. “It's everyone's favorite bogeyman, but they may be barking up the wrong tree.” Tol would direct more attention toward the prospect of rising sea levels, possibly sharply rising if the ice of West Antarctica accelerates its slipping into the sea (Science, 24 September 2004, p. 1897).

Others pointed to the possibility of sudden “regime shifts.” In these, the slowly strengthening greenhouse could abruptly snap climate patterns into new configurations. Such climatic switches have happened in the past, Severinghaus noted. The central United States seems to go through centuries-long intervals of longer and more frequent droughts separated by periods of less drought-prone climate. And there are signs that the recent western U.S. drought was intensified by the warming of tropical waters (Science, 31 January 2003, p. 636). Other climate regimes, such as the monsoons, might be susceptible to greenhouse-triggered shifts as well, noted physical oceanographer Lynne Talley of SIO. Abrupt surprises, it seems, may yet be found far beyond the North Atlantic.

↵*“Abrupt Climate Change: Mechanisms, Early Warning Signs, Impacts, and Economic Analyses,” held 9 to 15 July in Aspen, Colorado; organized by the Aspen Global Change Institute.

CLIMATE CHANGE

Hedging Your Climate-Change Bets

Richard A. Kerr

The prospects for sudden shifts in climate are highly uncertain. For some, that's justification for further study. But some economists disagree. To them, uncertainty is itself a reason to take action, and right away.

In a classic cost-benefit analysis, the immediate costs of dealing with profound uncertainty can be considerable. Unless decision-makers have a clear view of the future, economist Gary Yohe of Wesleyan University in Middletown, Connecticut, told workshop participants, the cost-benefit approach is likely to discourage any action.

Getting unstuck.

Treating climate-change mitigation as a form of insurance would buy time for scientists to sort out the risks.

ILLUSTRATION: TIM SMITH

But turned on its head, uncertainty can justify an alternative to cost-benefit analysis called risk management, an approach people take when they buy insurance. “Uncertainty is the reason you buy insurance,” says Yohe. Insurance does nothing to reduce the chances that your house will catch fire, he notes, but “it decreases the consequences should the bad event occur. People are willing to pay premiums for insurance because that spreads the risk.”

Under risk management, decision-makers would consider the range of possible outcomes and then try to avoid the worst by, for example, levying a tax on the carbon in fossil fuels that becomes the greenhouse gas carbon dioxide. The tax would reduce the urgency of making more sweeping decisions. At the same time, it would keep in play more ambitious goals such as holding greenhouse gases to even lower levels. All the while, scientists would be learning more about the risks of global warming.

Without much formal acknowledgement, decision-makers seem to be adopting risk management as they tackle global warming. Under the Kyoto Protocol, says Yohe, “the European approach to thinking about climate is based in large measure on risk management.” And in announcing goals for reducing greenhouse-gas emissions, the governor of California and a consortium of New England states seem to be thinking along the same lines. Perhaps the answer to climate uncertainty is doing what comes naturally.